Glycyrrhizic acid derivative and its use

Abstract

This invention provides a derivative of glycyrrhizic acid with no or reduced side effects. Furthermore, it provides an effective means for preventing the onset, improving, or slowing the progression of dementia, such as Alzheimer's disease. [Solution] To provide a pharmaceutical, quasi-drug, cosmetic, or food additive raw material containing 18α-glycyrrhizic acid or 18β-glycyrrhizic acid or licorice extract derived from licorice, for the purpose of preventing or slowing the progression of dementia.

Description

TECHNICAL FIELD

[0001] The present invention relates to a method of utilizing a glycyrrhizic acid derivative derived from licorice or a licorice extract. In particular, the present invention relates to a glycyrrhizic acid derivative and a method of using the same, particularly to a method for preventing or suppressing the progression of cognitive and memory disorders mainly typified by Alzheimer's disease by using a glycyrrhizic acid derivative derived from licorice or a licorice extract containing the same. BACKGROUND ART

[0002] Glycyrrhizic acid is a major saponin contained in the underground parts of plants belonging to the genus Glycyrrhiza of the legume family (such as Glycyrrhiza uralensis, G. glabra or G. inflata) that have been used as pharmaceuticals for a long time. At present, glycyrrhizic acid extracted and purified from the underground parts of Glycyrrhiza plants is incorporated into pharmaceuticals indicated for anti-inflammation, anti-allergy or anti-chronic hepatitis, or even into quasi-drugs and cosmetics that make use of its anti-inflammatory and anti-allergic effects. Furthermore, it is also used as a food additive that takes advantage of its sweet taste. Hitherto, more than 400 tons of glycyrrhizic acid per year has been consumed in Japan alone, but there have been safety issues. Namely, it is pseudoaldosteronism induced by glycyrrhizic acid.

[0003] For this reason, in the case of traditional Chinese medicine formulations containing glycyrrhizic acid, it is known that side effects are observed in proportion to the dose administered (Non-Patent Document 1), and the package inserts for pharmaceuticals containing glycyrrhizic acid are required to include descriptions that draw attention to the possibility of side effects occurring.

[0004] The symptoms of pseudoaldosteronism are hypertension and hypokalemia. This side effect results from glycyrrhetinic acid, which is a metabolite of ingested glycyrrhizic acid, or glycyrrhetinic acid 3-sulfate, which is its sulfate conjugate, inhibiting 11β-hydroxysteroid dehydrogenase type 2 present in the kidneys.

[0005] In other words, inhibition of this enzyme prevents the conversion of cortisol, the active form of glucocorticoid, to cortisone, the inactive form, leading to cortisol accumulation. It is thought that the increased cortisol acts on mineralocorticoid receptors in the renal tubules, promoting sodium reabsorption and increasing potassium excretion, thus making hypokalemia more likely.

[0006] When hypokalemia becomes severe, 1. it affects the cardiac conduction system and myocardial contractility, making arrhythmias more likely; 2. it causes an increase in creatinine kinase levels due to myopathy; 3. it affects the digestive system, causing paralytic bowel obstruction due to smooth muscle breakdown; and 4. it affects the kidneys, impairing the ability to concentrate urine and leading to a tendency towards polyuria.

[0007] Pseudoaldosteronism, on the other hand, presents with symptoms and findings similar to primary aldosteronism, such as hypertension, hypokalemia, metabolic alkalosis, and hypokalemic myopathy, but is characterized by decreased plasma aldosterone levels. Because it presents with hypertension accompanied by hypokalemia, the main symptoms include limb weakness, presumably due to hypokalemic myopathy, and a feeling of heaviness in the head associated with elevated blood pressure.

[0008] In light of these circumstances, there is a need for glycyrrhizic acid derivatives that do not cause side effects, or that have a reduced likelihood of causing side effects.

[0009] Incidentally, glycyrrhizic acid has isomers based on the arrangement of the hydrogen atom at position 18 in its molecule. Typically, more than 90% of the glycyrrhizic acid produced by licorice plants is the 18β form, but a small portion is the 18α form. The physiological activity of the 18α form is basically the same as that of the 18β form, but because it has a higher specific activity in anti-inflammatory and allergic effects, pharmaceuticals with the 18α form as the main component have been created. Furthermore, the 18α form differs from the 18β form in terms of physical properties; that is, it does not gel in acidic solutions like the 18β form, giving it the advantage of being able to be incorporated into relatively acidic cosmetics.

[0010] However, the inhibitory activity of 18α-glycyrrhetinic acid against 11β-hydroxysteroid dehydrogenase type 2, which is known to cause pseudoaldosteronism, has not been sufficiently investigated, and there are still some unknowns.

[0011] Specifically, according to Classen-Houben et al. (2009), 18α-glycyrrhetinic acid strongly inhibits rat-derived 11β-hydroxysteroid dehydrogenase type 2, but its inhibition of human-derived 11β-hydroxysteroid dehydrogenase type 2 is weak (Non-Patent Literature 2). On the other hand, according to Sanna et al. (2016), 18α-glycyrrhetinic acid inhibits both rat-derived and human-derived 11β-hydroxysteroid dehydrogenase type 2 to a similar degree (Non-Patent Literature 3).

[0012] Because there are papers that present such conflicting information, there has been no clear understanding in academia or industry regarding the side effects of 18α-glycyrrhetinic acid or glycyrrhizic acid until now. Similarly, the inhibition of the enzyme by each isomer due to species differences has also remained the same until now.

[0013] Incidentally, previous papers on the physiological activity of 18α-glycyrrhizic acid have only mentioned its strong activity as a distinguishing feature, with no mention of side effects (referenced papers 4-18). Rather, it has only been suggested that the rapid excretion of 18α-glycyrrhizic acid and its metabolite, 18α-glycyrrhetinic acid, from the body may reduce side effects due to its accumulation in the body (referenced paper 19).

[0014] In recent years, in developed countries including Japan, the number of patients with impaired brain function, such as those suffering from cerebral infarction, head injuries, cognitive and memory impairments like Alzheimer's disease and Parkinson's disease, and depression and anxiety disorders caused by various stresses, has been increasing and has become a social problem. Alzheimer's disease is a neurodegenerative disease that accounts for 50-60% of dementia cases. The neuropathological characteristics of Alzheimer's disease are neurofibrillary degeneration, senile plaques, and massive loss of nerve cells in the cerebral cortex and hippocampus. Neurofibrillary degeneration is caused by excessive phosphorylation of tau protein, one of the microtubule-associated proteins, resulting in the formation of fibrillary inclusions, while senile plaques are extracellular accumulations of amyloid-beta protein. In Alzheimer's disease, this accumulation of amyloid-beta protein accelerates neurofibrillary degeneration, and the fibrillated tau protein inhibits intracellular transport. Furthermore, amyloid-beta protein itself has cytotoxic properties, such as causing synaptic dysfunction.

[0015] Currently, there is no cure for Alzheimer's disease, but pharmaceuticals aimed at improving or suppressing its symptoms have already been reported (for example, Patent Documents 1 and 2).

[0016] With the arrival of a super-aging society, there are concerns that the number of dementia patients will increase dramatically, becoming a significant social problem. Therefore, there is a growing need for research into preventing, improving, and slowing the progression of dementia, such as Alzheimer's disease, particularly through interventions in lifestyle habits, including diet.

[0017] Incidentally, glycyrrhizic acid is known for its anti-allergic and anti-inflammatory effects, and it is known to improve central nervous system disorders caused by brain damage and neuroinflammation through its anti-inflammatory effects (Non-patent documents 20 and 21). However, there are currently no descriptions regarding its use in preventing, improving, or slowing the progression of dementia. [Prior art documents] [Patent Documents]

[0018] [Patent Document 1] Japanese Patent Publication No. 2014-009214 [Patent Document 2] Special Announcement No. 2014-101324 [Non-licensed literature]

[0019] [Non-licensed Document 1] A survey of the literature on the amount of licorice used and the frequency of licorice syndrome, Naoki Wangani, Nitto Medical Journal Vol.66No.3 197-202, 2015 [Non-licensed Document 2] D. Classen-Houben et al. “Selective inhibition of 11β-hydroxysteroid dehydrogenase 1 by 18α-glycyrrhetinic acid but not 18α-glycyrrhetinic acid” Journal of Steroid Biochemistry & Molecular Biology 113 (2009) 248-252 [Non-licensed Document 3] PP Sanna et. al., “11β-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse” Transl Psychiatry (2016) 6, e760 [Non-licensed Document 4] Chengxi Cai et. al., "Clinical Observation of Magnesium Isoglycyrrhizinate in Treatment of HBV-Related Liver Cirrhosis" Traditional Chinese Medicine, 2016, 5(3), 91-96 [Non-licensed Document 5] Yang, et. al. "A melioration of concanavalin A-induced autoimmune hepatitis by magnesium isoglycyrrhizinate through inhibition of CD4+CD25-CD69+ subset proliferation" Drug Design, Development and Therapy 2016:10 Non-Patent Document 6 WU et. al. "Magnesium isoglycyrrhizinate ameliorates doxorubicin-induced acute cardiac and hepatic toxicity via anti-oxidant and anti-apoptotic mechanisms in mice" EXPERIMENTAL AND THERAPEUTIC MEDICINE 15: 1005-1012, 2018 Non-Patent Document 7 ZOU et. al. "Magnesium isoglycy has hepatoprotective effects in an oxaliplatin-induced model of liver injury" INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 42: 2020-2030, 2018 Non-Patent Document 8 Tang GH et al., "Magnesium isoglycyrrhizinate inhibits inflammatory response through STAT3 pathway to protect remnant liver function" World J Gastroenterol 2015 November 21; 21(43): 12370-12380 Non-Patent Document 9 Q. Y. TAN ET AL. "Licorice root extract and magnesium isoglycyrrhizinate protect against triptolide-induced hepatotoxicity via up-regulation of the Nrf2 pathway" DRUG DELIVERY 2018, VOL. 25, NO. 1, 1213-1223 Non-Patent Document 10 Qu Y et. al., "18a-Glycyrrhizin induces apoptosis and suppresses activation of rat hepatic stellate cells" Med Sci Monit, 2012: 18(1): BR24-32 Non-Patent Document 11 Y.He et. al., "Protective Effect of Magnesium Isoglycyrrhizinate on Ethanol-Induced Testicular Injuries in Mice" Journal of Biomedical Research, 2010, 24(2):153-160 Non-Patent Document 12 Wenjiao J et. al., "Magnesium isoglycyrrhizinate shows hepatoprotective effects in a cyclophosphamide-induced model of hepatic injury" Oncotarget, 2017, Vol. 8, (No. 20), pp: 33252-33264 Non-Patent Document 13 Z.W. Xiao et. al., "Therapeutic effect of magnesium isoglycyrrhizinate in rats on lung injury induced by paraquat poisoning" European Review for Medical and Pharmacological Sciences 2014; 18: 311-320 Non-Patent Document 14 Xinli H et. al., "Magnesium isoglycyrrhizinate protects hepatic L02 cells from ischemia / reperfusion induced injury" Int J Clin Exp Pathol 2014;7(8):4755-4764 Non-Patent Document 15 Tee et. al., "Magnesium Isoglycyrrhizinate Ameliorates Fibrosis and Disrupts TGF-β-Mediated SMAD Pathway in Activated Hepatic Stellate Cell Line LX2" September 2018|Volume 9 Article 1018 Non-Patent Document 16 J. Zheng et al. "Protective effects against and potential mechanisms underlying the effect of magnesium isoglycyrrhizinate in hypoxia-reoxygenation injury in rat liver cells" Genetics and Molecular Research 14 (4): 15453-15461 (2015) Non-Patent Document 17 Q. Yang, et al. "Magnesium isoglycyrrhizinate ameliorates radiation-induced pulmonary fibrosis by inhibiting fibroblast differentiation via the p38MAPK / Akt / Nox4 pathway" Biomedicine & Pharmacotherapy 115 (2019) 108955 Non-Patent Document 18 HUO et al., "Optimal ratio of 18α- and 18β-glycyrrhizic acid for preventing alcoholic Hepatitis in Rats" MENTAL AND THERAPEUTIC MEDICINE 18: 172-178, 2019 Non-Patent Document 19 Xu et al., "Comparison of the Exposure of Glycyrrhizin and its Metabolites and the Pseudoaldosteronism after Intravenous Administration of Alpha- and Beta-glycyrrhizin in Rat" Drug Research 13: 620-624, 2013 Non-Patent Document 20 Y.Li et al. (2019) Glycyrrhizin, an HMGB1 inhibitor, exhibits neuroprotective effects in rats after lithium-pilocarpine-induced status epilepticus. J. Pharm. Pharmacol. 71, 390-399. Non-Patent Document 21 W.Liu et al. (2019) Suppressive effects of glycyrrhizic acid against lipopolysaccharide-induced neuroinflammation and cognitive impairment in C57 mice via toll-like receptor 4 signaling pathway. Food Nutr. Res. DOI: 10.29219 / fmr.v63.1516. [Overview of the Initiative] [Problems that the invention aims to solve]

[0020] The object of the present invention is to provide a derivative of glycyrrhizic acid that has no or reduced side effects. Furthermore, it is to provide an effective means for preventing the onset, improving, or slowing the progression of dementia, such as Alzheimer's disease. [Means for solving the problem]

[0021] To solve the aforementioned problems, the inventors re-examined the inhibitory activity of 18α-glycyrrhetinic acid, the aglycone of 18α-glycyrrhizic acid, an isomer of 18β-glycyrrhizic acid that is commonly used, and confirmed that the side effects of 18α-glycyrrhizic acid are reduced, finding that it can be used as a safe ingredient for pharmaceuticals, quasi-drugs, or food additives. Furthermore, 18α-glycyrrhetinic acid, which consists only of the aglycone obtained by cleaving the sugar portion of 18α-glycyrrhizic acid, or 18-α-glycyrrhetinic acid-3-O-monoglucuronide, which retains only one sugar, also have anti-inflammatory and allergic effects, and these can also be used in the present invention. Furthermore, the inventors focused on 18α-glycyrrhizic acid, which has reduced side effects, and in order to solve the aforementioned problems related to dementia such as Alzheimer's disease, they conducted a cognitive decline inhibition test of glycyrrhizic acid in Alzheimer's disease model animals. They were the first to discover that glycyrrhizic acid strongly inhibits cognitive decline, and based on this finding, completed the present invention. That is, the pharmaceutical composition of this invention is a pharmaceutical composition for the treatment of neurological diseases, the prevention of neurological diseases, or the improvement of brain function, and contains glycyrrhizic acid or a related substance therein as an active ingredient. The pharmaceutical composition of this invention may also be licorice extract itself, or glycyrrhizic acid or a related substance extracted and purified from licorice, or a salt thereof.

[0022] [1] The following structural formula: [ka] [ka] [ka] A pharmaceutical, quasi-drug, cosmetic or food additive ingredient comprising at least one selected from the group consisting of compounds represented by, salts thereof, and solvations thereof, for the treatment of neurological diseases, prevention of neurological diseases, or improvement of brain function. [2] The following structural formula: [ka] A pharmaceutical, quasi-drug, cosmetic or food additive raw material according to [1], comprising at least one selected from the group consisting of compounds represented by, salts thereof, and solvations thereof. [3] The pharmaceutical, quasi-drug, cosmetic or food additive raw material described in [1] or [2] for use in humans. A pharmaceutical, quasi-drug, cosmetic or food additive raw material, or sweetener food additive for anti-inflammatory and anti-allergic purposes, containing 0.1-1% of the compound described in [4][1] or [2]. [5] A pharmaceutical, quasi-drug, cosmetic, or food additive ingredient described in any of [1] to [4], or a sweetener food additive, for the prevention of dementia or the progression of dementia. [6] A pharmaceutical, quasi-drug, cosmetic or food additive ingredient, or sweetener, as described in [5], whose target is human. [Effects of the Invention]

[0023] According to the present invention, it is possible to provide pharmaceuticals, quasi-drugs, cosmetics, or food additives that utilize their sweetness, or highly safe dementia preventive drugs, that have higher safety for living organisms and take advantage of anti-inflammatory and allergic effects. The pharmaceutical composition of this invention uses glycyrrhizic acid, which has been used for a long time, as an active ingredient, and even with the conventionally used 18β-glycyrrhizic acid, it is possible to provide dementia preventive drugs that are highly safe even when taken over a long period of time at normal dosages. [Brief explanation of the drawing]

[0024] [Figure 1] This is a comparison of memory and learning abilities using a step-through method. [Figure 2] Accumulation of phosphorylated tau protein in the hippocampus (Figure 3). Accumulation of amyloid-beta in the hippocampus. [Figure 3] This is the accumulation of amyloid-beta in the hippocampus of the brain. [Figure 4] This is the concentration of short-chain fatty acids in the feces of aging-accelerated mice. [Figure 5] This is the percentage of gut bacterial species present in aging-accelerated mice. [Modes for carrying out the invention]

[0025] In the present invention, 18α-glycyrrhizic acid, 18α-glycyrrhetinic acid, and 18α-glycyrrhetinic acid-3-O-monoglucuronide refer to saponins obtained by synthesis from 18β-glycyrrhizic acid, which is a saponin derived from a plant belonging to the genus Glycyrrhiza. In addition, 18β-glycyrrhizic acid itself, or licorice extract containing it, can also be used for dementia prevention. That is, the composition may be either 18β-glycyrrhizic acid itself or licorice extract containing 18β-glycyrrhizic acid. The 18β-glycyrrhizic acid used in the present invention can be obtained by extraction, isolation, and purification from licorice extract using a general method. That is, after removing lipid-soluble coloring components from licorice extract by organic solvent extraction, a purified product with a purity of 70% or more can be obtained by purification using means such as crystallization. On the other hand, when using licorice extract, the roots and / or stems of the plant can be processed as appropriate and used. In the present invention, commercially available licorice extract may be used, or licorice extract manufactured by methods known in the art may be used. The licorice extract used in the present invention has a 18β-glycyrrhizic acid content of 5% or more, preferably 10% or more, and more preferably 13% or more.

[0026] The solvent used for extracting licorice extract is not particularly limited, but for example, water, alcohol (e.g., methanol, ethanol, n-propanol, n-butanol, etc.), acetone, ethyl acetate, etc. can be used. Furthermore, when obtaining the dried powder, it can be obtained by removing the solvent from the extract by methods commonly used by those skilled in the art, such as vacuum drying or spray drying.

[0027] To produce 18α-glycyrrhizic acid from 18β-glycyrrhizic acid, as described in, for example, the patent publication (No. 1610300: registered July 15, 1990), the raw material, 18β-glycyrrhizic acid, is heated at 70-200°C under atmospheric pressure or pressurized pressure in an aqueous solution of sodium hydroxide or potassium hydroxide of about 2-6N. The reaction is stopped when isomerization reaches 60-80%, and then the resulting 18α-glycyrrhizic acid and 18β-glycyrrhizic acid are separated. This yields 18α-glycyrrhizic acid of the desired purity. To isolate 18α-glycyrrhizic acid from the reaction mixture, the 18α and 18β areomers are first precipitated together with a mineral acid such as sulfuric acid or hydrochloric acid to a pH of 1-2, the precipitate is filtered, and then fractionated by column chromatography or the like. Alternatively, the method for isolating only the 18α isomer is as follows.

[0028] A dilute aqueous solution of glycyrrhizic acid mixture with a concentration of about 0.5-2% is prepared, and mineral acid is added to adjust the pH to about 2. The mixture is then dissolved using a paper filter. In this case, the 18α-form is acid-precipitationd in a crystalline state and remains on the paper filter, while the 18β-form separates into a gel-like state and passes through the paper filter, thus entering the filtrate. A considerable amount of 18β-form still remains in the precipitate on the paper filter, so this is dissolved in dilute ammonia water, and then the separation by acid precipitation and filtration is performed again. By repeating this process, the purity of the 18α-form increases, and the removal of the 18β-form is usually completed after 3-5 repetitions.

[0029] Applications of the agent of the present invention in biological applications: Potential applications include pharmaceuticals, quasi-drugs, cosmetics, and food products. However, the preferred target population in these cases is humans. For example, while rodents such as rats and mice do not develop pseudoaldosteronism, they inhibit 11β-hydroxysteroid dehydrogenase type 2 derived from these animal species, making them undesirable. Furthermore, inhibition tests against enzymes derived from livestock such as cattle, horses, sheep, and goats have not been conducted, so their suitability cannot be determined.

[0030] The form of the agent of the present invention is not particularly limited, and can take any form that is commonly used in each application, depending on the application of the agent of the present invention.

[0031] In terms of form, when used as a pharmaceutical, various forms are considered, including injections and oral preparations. For quasi-drugs, it can be added to toothpaste and other products. For cosmetics, it can be added to various dosage forms, similar to 18β-dipotassium glycyrrhizinate. For food additives, it is expected to be used in the same way as the 18β form.

[0032] The dosage of 18α-glycyrrhizic acid and 18β-glycyrrhizic acid in the pharmaceuticals of the present invention is 5 to 120 mg / day / human, preferably 10 to 60 mg / day / human. In this case, the above dosage is divided and administered two to three times a day. When using licorice extract, the dosage should be adjusted to be similar to that of glycyrrhizic acid, taking into account the glycyrrhizic acid content. [Examples]

[0033] The following is an overview of the method for measuring the inhibition of human 11β-hydroxysteroid dehydrogenase type 2 by the test substance. Specifically, 250 μL of 0.1 M phosphate buffer (pH = 6.0) containing rat kidney microsomal fraction (final concentration 2 mg / mL), 1,2,6,7-[3H]-cortisol (Perkin Elmer, Waltham, MA, USA) 20 nM, NAD+ (Fujifilm) 1.2 mM, and various samples was prepared. Alternatively, 25 μL of 0.1 M phosphate buffer (pH = 6.0) containing rat kidney microsomal fraction (final concentration 2 mg / mL) or human kidney microsomal fraction (SekisuiXenoTech, Kansas City, KA, USA) (final concentration 0.2 mg / mL), 1,2,6,7-[3H]-cortisol 20 nM, NAD+ 1.2 mM, and various samples was prepared. After incubating each mixture at 37°C for 30 minutes, 25 μL of methanol containing 1 mg / mL cortisol and 1 mg / mL cortisone (Nacalai Tesque, Kyoto) was added to the reaction mixture to stop the reaction.

[0034] 20 μL of this liquid was spotted onto a thin-layer chromatography plate (Silica Gel 60, Merck, Darmstadt, Germany), and developed on approximately 18 cm with chloroform:methanol (9:1) to separate cortisol and cortisone. The cortisone spot (Rf value approximately 0.43) was identified under a UV lamp, scraped off, and transferred to a vial containing 3 mL of Clear-sol I (Nacalai). Radioactivity was measured using a liquid scintillation counter. Each sample consisted of n=4, and the mean standard deviation was used as the data. For the IC50 value, three points were used that surround 50% of the inhibition rate, and the concentration that showed 50% on the approximation line between logarithmic concentration and inhibition rate was calculated.

[0035] As a result, the findings shown in Table 1 were obtained. In the case of 18β-glycyrrhetinic acid, a 50% inhibition rate was achieved at concentrations of 0.2-0.4 μM for both human and rat-derived enzymes. In contrast, for 18α-glycyrrhetinic acid, a 50% inhibition rate was achieved at the same concentration as for the 18β-form for rat-derived enzymes, but it was approximately 70 times higher at 15.1 μM for human-derived enzymes, confirming that it poses a low risk of causing pseudoaldosteronism in humans. [Table 1] [Examples]

[0036] The following is an overview of the method for measuring the dementia-preventive effect of the test substance. Specifically, 40-week-old SAMP8 aging mice were used as test animals and were reared for 12 weeks. SAMR1 normal mice were used as the control group. They were given normal water and food. These mice were orally administered 18α-glycyrrhizic acid or 18β-glycyrrhizic acid at a dose of 15 mg / kg three times a week. A spontaneous movement measurement device was used to quantify and measure the amount of activity using an infrared sensor attached to the bottom of the cage. Each test mouse was placed in a new environment one at a time (without training), and the amount of spontaneous movement of each mouse was measured for 20 minutes. Learning and memory test using passive avoidance experiment: Mice are subjected to an electric current when they enter a dark box to induce learning. After one day, the mice are placed in a bright box and the time they spend in the bright box is measured. If learning and memory have been established, the mice will not want to enter the dark box and the time they spend in the bright box will increase.

[0037] Weight changes: SAMP8 mice were significantly lighter than SAMR1 mice. A tendency towards age-related weight loss was observed in SAMP8 mice. While no effect was observed from glycyrrhizin administration, it did tend to mitigate the age-related weight loss trend. In the passive avoidance experiment, SAMP8 mice showed reduced learning and memory abilities, with no difference observed between the acquisition trial (a test during learning) and the playback trial (a test based on memory one day later). On the other hand, in each glycyrrhizic acid administration group of SAMP8 mice, the step-through latency time (time spent in the light box) increased in the playback trial (P<0.05). Thus, the results of comparing memory and learning abilities using the step-through test as one of the dementia tests are shown in Figure 1. Specifically, in the glycyrrhizic acid administration groups, both the 18α and 18β forms resulted in a light box stay time that was more than three times longer than that of the non-administered group, indicating a significant improvement in memory and learning ability. Immunohistochemical staining results (18α-isomer is under investigation): The accumulation of phosphorylated tau protein (Figure 2) and amyloid-beta (Figure 3), which are pathologically important in Alzheimer's disease, in mouse brain tissue was suppressed in the group administered 18β-glycyrrhizic acid. Regarding the concentration of short-chain fatty acids in feces, the concentrations of acetic acid and propionic acid, which are among the short-chain fatty acids that are thought to decrease in people with Alzheimer's disease, were higher in the group administered 18β-glycyrrhizic acid (Figure 4). Intestinal bacterial species in feces (18α-is under investigation): The proportion of Coriobacterioceae, Alphaproteobacteria, and Paraprevoteraceae, which are known to increase in the feces of Alzheimer's disease patients, was decreased in the glycyrrhizic acid administration group. Conversely, the proportion of Bacteroides and Parabacteroides, which are known to decrease in the feces of Alzheimer's disease patients, was increased in the 18β-glycyrrhizic acid administration group (Figure 5). [Industrial applicability]

[0038] The 18α-glycyrrhizic acid of the present invention is highly safe for humans and, as a more active glycyrrhizic acid derivative, is useful as a raw material for pharmaceuticals, quasi-drugs, cosmetics, or food additives. Furthermore, dementia preventive agents containing 18α-glycyrrhizic acid or 18β-glycyrrhizic acid are useful for preventing the onset or progression of Alzheimer's disease in humans.

Claims

1. The following structural formula: 【Transformation 5】 【Transformation 6】 【Transformation 7】 A pharmaceutical, quasi-drug, cosmetic, or food additive raw material for the treatment of neurological diseases, prevention of neurological diseases, or improvement of brain function, comprising at least one selected from the group consisting of compounds represented by, salts thereof, and solvations thereof.

2. The following structural formula: 【Transformation 8】 A pharmaceutical, quasi-drug, cosmetic or food additive raw material according to claim 1, comprising at least one selected from the group consisting of compounds represented by, salts thereof, and solvations thereof.

3. A pharmaceutical, quasi-drug, cosmetic, or food additive raw material according to claim 1 or claim 2, for use in humans.

4. A pharmaceutical, quasi-drug, cosmetic, or food additive raw material, or sweetener, for anti-inflammatory and anti-allergic purposes, comprising 0.1 to 1% of the compound described in claim 1 or claim 2.

5. A pharmaceutical product, quasi-drug, cosmetic product, or food additive raw material, or sweetener food additive, according to any one of claims 1 to 4, for the purpose of preventing dementia or slowing the progression of dementia.

6. A pharmaceutical product, quasi-drug, cosmetic product, or food additive raw material, or sweetener food additive according to claim 5, wherein the target is human.

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